Growth hormone (GH) is produced in somatotroph cells of the anterior pituitary gland of mammals and secreted throughout life. It is mainly controlled in the brain by two hypothalamic peptides: GRF, which stimulates its secretion and synthesis; and somatostatin, which inhibits them. A number of peripheral factors regulate GH secretion. Among them, insulin-like growth factor-1 (IGF-1) represents an important one as it is produced by the liver in response to GH and acts on the hypothalamus to exert a negative feedback on GH secretion.
The decrease of GH secretion with age, demonstrated in humans and animals, favors a metabolic shift towards catabolism which initiates or participates in the aging of an organism. Loss of muscle mass, accumulation of adipose tissue, bone demineralization, and loss of tissue regeneration capacity after injury, which are observed in the elderly, correlate with the decrease in the secretion of GH.
GH is thus a physiological anabolic agent that is involved in the linear growth of children and which controls protein metabolism in adults.
GRF (also referred to as GH releasing hormone or GHRH) is a 44 amino acid peptide secreted by the hypothalamus that regulates the expression, synthesis and release of GH from the somatotroph cells of the anterior pituitary (Frohman L A et al. Endocrine Reviews 1986, 7: 223-253). A peptide consisting of the first 29 amino acids of human GRF (hGRF(1-29); sermorelin) retains the biological activity of the full-length peptide (Lance, V. A. et al., Biochemical and Biophysical Research Communications 1984, 119: 265-272) and has been used clinically for the treatment of GH deficiency in children (Thorner, M. et al., Journal of Clinical Endocrinology and Metabolism 1996, 81: 1189-1196). More recently, the potential of GRF to reverse the age-related decline in the function of the somatotrophic GH-insulin-like growth factor (IGF)-I axis has been evaluated (Khorram, O. et al., Clinical Obstetrics and Gynecology 2001, 44: 893-901).
A pharmaceutical preparation of hGRF(1-29) has been available for clinical use (Geref®, Laboratoires Serono S.A.). However, its pharmacological value is limited by its short half-life (approximately 12 min. following intravenous injection in humans), mainly due its susceptibility to rapid enzymatic degradation (Frohman, L. A. et al., Journal of Clinical Investigation 1986, 78: 906-913).
There is thus a need for the development of novel GRF analogs exhibiting agonist properties toward the GRF receptor or GHRH receptor (GHRHr).
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.